A comparative study of the relationship between histocompatibility and pregnancy in the genus Equus is proposed. The focus of the project is to elucidate the development and function of and immune responses surrounding the equine endometrial cups, which constitute the invasive portion of equine trophoblast. The basic hypothesis is that the endometrial cups have a hitherto undetected immunoregulatory role in equine pregnancy in addition to their well-known endocrine function as the source of equine chorionic gonadotrophin. The research will have 2 principal components which are integrally related. First, maternal immune responses to Major Histocompatibility Complex (MHC) antigens during equine pregnancy will be investigated. Well-characterized alloantisera and monoclonal antibodies which recognize equine MHC antigens will be used in conjunction with immunohistochemical methods, tissue culture, and experimental matings to determine the source of fetal MHC antigens which stimulate the maternal cytotoxic antibody response in early equine pregnancy. The segregation behavior of equine MHC antigens will be investigated in populations of breeding horses on commercial farms. If there are important consequences of maternal immune responses to MHC antigens (or lack of such responses), they should be discernible in horses, where the evidence for maternal antifetal immune responses is stronger than in any other studied species. Second, the function of the endometrial cups will be studied using several approaches. The donkey-in-horse extraspecies pregnancy will be investigated as a model of immunologically mediated abortion. Immunization therapy will be developed that can protect such pregnancies, which lack endometrial cups. These experiments have direct relevance to experimental immunization regimes which are currently under evaluation for women with histories of repeated spontaneous abortion. Monoclonal antibodies to endometrial cup-specific molecules of the horse will be used to characterize the structure and function of those molecules in in vitro and in vivo experiments. Interspecies pregnancies will be established to amplify particular aspects of the endometrial cup reaction. These experiments should provide important information about the function of invasive trophoblast in placental development and the maintenance of pregnancy.